Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genodermatosis caused by mutations in the COL7A1 gene resulting in skin blistering, and a high risk of developing Squamous Cell Carcinomas (SCC). Unlike sporadic SCC, which usually have favorable outcome, SCC from patients with RDEB become rapidly metastatic with a mortality of 80% within 5 years from primary tumor diagnosis. Mechanisms explaining this different behavior are not fully understood, but recently, alterations of the stroma rise as primary determinants for aggressive SCC development. The cellular and molecular research that led to this hypothesis has been described, but a careful revision of the histopathological characteristics of the SCC-RDEB stroma is missing. In this study, we have characterized SCC biopsies from 20 RDEB-SCC and from sporadic SCC, with focus on the tumor stroma. A wide range of ages and severity was chosen to perform this study.Both types of tumors showed variable patterns of growth and grading. Most of the SCC-RDEB tumors are surrounded by dermal fibrosis, which is rich in coarse bundles of collagen fibers, as a result of the chronic wound healing process, characteristic of RDEB patients. Moreover, in 90% of RDEB-SCC, the tumoral stroma also showed a similar collagenous fibrotic reaction.In some sporadic SCCs, collagenosis was present, but rarely to the extent observed in the RDEB-SCC. The existence of an inflammatory infiltrate was frequently present in both types of tumors. However, it is important to mention that a stroma with neither fibrosis nor inflammatory infiltration was only present in the sporadic tumors.Although there was great variability in both type of tumors, the clear tendency of RDEB-SCCs to exhibit a stronger fibrotic reaction support the hypothesis that a stiff collagenous stroma is, at least, one critical element in the aggressive behavior of RDEB-SCC.